Derivatives of 1-[3-(4-hydroxyphenyl) 1-hydroxy 1-propyl] benzene substituted in position 2 by an aminoalkyleneoxy chain, the method of preparing same and the application thereof to therapeutics

ABSTRACT

The present invention relates to compounds of formula: ##STR1## in which: R 3  is hydrogen, 2-tetrahydropyranyl or benzyl; 
     R 1  and R 2  are such that: 
     either R 1  represents a methoxy group in which case R 2  is a group chosen from the following: hydroxyl; C 1  -C 4  alkyl; C 2  -C 8  alkyloxy; C 5  -C 7  cycloalkloxy; benzyloxy; 
     or R 2  represents a methoxy group in which case R 1  is a group chosen from the following: hydroxyl; C 2  -C 8  alkyloxy; C 2  -C 8  alkyloxy substituted by a methoxy group; C 1  -C 4  trifluoroalkyloxy; C 3  -C 4  alkenyloxy; C 5  -C 7  cycloalkyloxy; benzyloxy; C 1  -C 4  alkylthio; 
     n=2 or 3; and 
     p=4, 5 or 6, 
     as well as their addition salts with mineral or organic acids, said compounds and salts being useful as drugs.

This is a division of Ser. No. 07/339,815, filed Apr. 18, 1989, now U.S. Pat. No. 5,017,572.

The present invention relates to new derivatives of 1-[3-(4-hydroxyphenyl) 1-hydroxy 1-propyl] benzene substituted in position 2 by an aminoalkyleneoxy chain, the method of preparing same and the application thereof to therapeutics.

More precisely, the derivatives of the invention correspond to the formula: ##STR2## in which: R₁ and R₂ are such that:

either R₁ represents a methoxy group in which case R₂ is a group chosen from the following: hydroxyl; C₁ -C₄ alkyl; C₂ -C₈ alkyloxy; C₅ -C₇ cycloalkyloxy; benzyloxy;

or R₂ represents a methoxy group in which case R₁ is a group chosen from the following: hydroxyl; C₂ -C₈ alkyloxy; C₂ -C₈ alkyloxy substituted by a methoxy group; C₁ -C₄ trifluoroalkyloxy; C₃ -C₄ alkenyloxy; C₅ -C₇ cycloalkyloxy; benzyloxy; C_(1-C) ₄ alkylthio;

n=2 or 3; and

p=4, 5 or 6.

The invention also relates to the acid addition salts of these derivatives, these salts being formed with mineral acids such as hydrochloric, sulphuric or phosphoric acid or with organic acids such as fumaric, maleic, succinic, oxalic, citric or tartaric acid.

In the foregoing and in what follows the expression "C₁ -C₄ alkyl" includes in particular, methyl, ethyl, n-propyl and n-butyl groups; the expression "C₂ -C₈ alkyloxy" includes particularly, ethoxy, n-propyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy, n-heptyloxy and n-octyloxy groups; the expression "C₅ -C₇ cycloalkyloxy" includes cyclopentyloxy, cyclohexyloxy and cycloheptyloxy groups; the expression "C₃ -C₄ alkenyloxy" includes in particular, OCH₂ --CH═CH₂, OCH₂ --CH═CH--CH₃ and OCH₂ --CH₂ --CH═CH₂ groups; and the expression "C₁ -C₄ alkylthio" includes particularly, methoxythio, ethylthio, n-propylthio and n-butylthio groups.

The present invention further relates to methods of synthesizing the derivatives of formula (I), these methods being in accordance with the reaction diagrams hereafter. ##STR3##

In the above reaction diagrams, the parameters appearing in formulae (II) to (XX) have the following meanings:

n=2 or 3,

p=4, 5 or 6,

R₃ =H, 2-tetrahydropyranyl or benzyl,

R₁₀ and R₂₀ have respectively the same meaning as R₁ and R₂ in the formula (I) with the exception of the benzyloxy group,

R₁₁ and R₂₁ have respectively the same meaning as R₁ and R₂ in the formula (I) with the exception of the hydroxyl group,

R₂₁₀ =C₂ -C₈ alkyl or C₅ -C₇ cycloalkyl,

Y=halogene, OSO₂ CH₃ or OSO₃ C₂ H₅,

R₁₁₀ =C₂ -C₈ alkyloxy or C₃ -C₄ trifluoroalkyloxy,

Ms=mesyl,

THP: 2-tetrahydropyranyl,

R₁₂ and R₂₂ are such that either R_(12=OCH3) in which case R₂₂ =benzyloxy, or R₂₂ =OCH₃ in which case R₁₂ =C₂ -C₈ alkyloxy, C₂ -C₈ alkyloxy substituted by a methoxy group, C₃ or C₄ alkenyloxy, C₅ -C₇ cycloalkyloxy, benzyloxy or C₁ -C₄ alkylthio,

R₂₃ =OCH₃ or benzyloxy,

X=Br or I.

Furthermore, the indices 1 to ○23 appearing in these reaction diagrams have the following meanings:

1 Reduction by sodium borohydride, particularly in an alcohol preferably ethanol medium, in the presence of a base, e.g. NaOH,

2 Hydrogenation, particularly in ethanol, in the presence of acid palladium on charcoal,

3 Reduction by sodium borohydride in ethanol in the presence of pyridine and NaOH,

○3a Reduction by sodium borohydride in ethanol followed either by acid hydrolysis when R₃ =2-tetrahydropyranyl, or hydrogenolysis in the presence of palladium on charcoal in ethanol when R₃ =benzyl,

4 Condensation of the benzaldehyde of formula: ##STR4## on the compounds (IV) in an alkaline medium in ethanol; when R₃ =H, 5 equivalents of 50% NaOH are preferably used whereas when R₃ =benzyl or 2-tetrahydropyranyl, 2.5 equivalents of 40% NaOH are sufficient,

5 Condensation of the compound of formula: ##STR5## preferably in the form of hydrochloride, on the compounds (V) for which R₂₂ =methoxy and R₁₂ =C₂ -C₈ alkyloxy, C₂ -C₈ alkyloxysubstituted by methoxy, C₃ or C₄ alkenyloxy, C₅ -C₇ cycloalkyloxy, benzyloxy or C₁ -C₄ alkylthio, preferably in an aprotic organic solvent such as acetonitrile and in the presence of alkaline metal carbonates such as potassium carbonate,

6 O-alkylation preferably in an organic solvent such as acetonitrile and in the presence of a base such as potassium carbonate,

7 Debenzylation by action of hydrogen in the presence of acid palladium on charcoal in an ethanol medium,

8 Condensation of the compound of formula: ##STR6## preferably in the form of hydrochloride, on compounds (V) for which R12=OCH₃ and R₂₂ =benzyloxy, under the operating conditions as in step 5,

9 Condensation with the amine of formula: ##STR7## used in excess and at reflux, ○10 Action of mesyl chloride in an organic solvent in the presence of triethylamine when cold,

○11 Condensation on the compounds (X) of trifluoro (C₁ -C₄) alkyl triflate in acetone in the presence of K2co₃ or of a C₂ -C₈ alkyl halide in DMF in the presence of K2co₃, followed by acid hydrolysis,

○12 Action of hydrogen in the presence of palladium on charcoal in ethanol,

○13 Action of the compound of formula: ##STR8## in acetonitrile in the presence of K₂ CO₃ on the compounds (V) for which (R₁₂, R₂₂)=(OCH₂ φ, OCH₃),

○14 Demethylation by aluminium chloride, preferably in dichloromethane,

○15 Condensation with 2 equivalents of CH₃ MnI in ethyl ether,

○16 Action of thionyl chloride in toluene,

○17 Action of bromine, in the presence of aqueous NaOH, followed by acidification by H₂ SO₄ at reflux,

○18 Condensation with one equivalent of CH₃ MnI in ethyl ether,

○19 Action of thionyl chloride in toluene,

○20 Alkylation by a C₁ -C₄ alkyl halide in the presence of 2 equivalents of n-butyllithium,

○21 Condensation with compounds of formula:

    R.sub.120 -O-Na or

    R.sub.121 -S-Na

where R₁₂₀ =C₂ -C₈ alkyl; C₂ -C₈ alkyl substituted by methoxy; C₃ or C₄ alkenyl; C₅ -C₇ cycloalkyl; or benzyl, and R₁₂₁ =C₁ -C₄ alkyl, in the presence of CuI (when R₁₂₀ ONa is used) or Cu₂ O (when R₁₂₁ SNa is used),

○22 Action of bromine in CHCl3 or iodine chloride in acetic acid,

○23 O-alkylation by action of benzyl chloride or bromide or methyl sulphate, in acetone in the presence of K₂ CO₃.

The compounds (I) for which R₁ =OH may further be prepared by hydrogenolysis with palladium on charcoal, in an ethanol medium, of the corresponding compounds (I) for which R₁ =O-CH₂ φ.

The salts of the derivatives of formula (I) are obtained conventionally, for example, by the action of a mineral or organic acid, in solution with an appropriate solvent, on said derivatives themselves, in solution with an appropriate solvent.

The following preparations are given by way of non limitative examples for illustrating the invention.

EXAMPLE 1 2-Hydroxy 6-methoxy acetophenone [(XX); R₂₃ =OCH₃ ] Code Number: 9

A mixture of 25 mmoles of 2,6-dihydroxy acetophenone, 26 mmoles of methyl sulphate, 75 mmoles of K2CO₃ and 60 ml of acetone are heated to reflux for 12 hours. Then the reaction medium is cooled, the mineral matter is separated by filtration and rinsed with dichloromethane. After evaporation of the organic phase and flash chromatography, the expected product is obtained in a practically quantitave way (mp=55° C.).

With the same operating conditions, but using benzyl bromide in place of 2,6-dihydroxy acetophenone, 2-hydroxy 6-methoxy acetophenone [(XX), R₂₃ =OCH₂ φ; code number 42] is obtained with a yield of 60% (mp=109° C.).

EXAMPLE 2 3-Bromo 2-hydroxy 6-methoxy acetophenone [(XIX); X=Br, R₂₃ =OCH₃] Code Number: 10

By action of the bromine on the compound of code number 9 prepared in the preceding example, in methylene chloride, using the technique described by C. L. COON, W. G. BLUTCHER, M. E. HILL, J. Org. Chem. 38, 4243 (1973), the expected compound is obtained with a yield of 76% (mp=101° C.).

In the same way, but starting with the compound of code number 42, 3-bromo 2-hydroxy 6-benzyloxy acetophenone is obtained [(XIX), R₂₃ =OCH₂ φ, X=Br; code number 43] with a yield of 84% (mp=124° C.; IR_(KBr) ; peak CO at 1620 cm⁻¹).

EXAMPLE 3 2-Hydroxy 3-iodo 6-methoxy acetophenone [(XIX); R₂₃ =OCH₃, X=I] Code Number: 13

409 g (2.45 moles) of acetophenone of code number 9 prepared in example 1 is solubilized in 3 liters of crystallizable acetic acid. At the same time, 420 g (2.60 moles) of iodine chloride are solubilized in 400 ml of acetic acid. At 17° C., the iodine chloride solution is added in 15 minutes to the solution of the acetophenone. After 10 minutes agitation, the reaction is finished. Then the mixture obtained is poured on 10 liters of cold water and the whole is agitated for 30 minutes, then filtered, drained, rinsed with 2 liters of water, drained, dried for 1 hour 30 minutes in a ventilated oven at 50° C. and the product is recrystallied in ethanol to isolate 634 g (yield=88%) of the expected compound.

melting point=115° C.,

IR_(KBr) : peak CO at 1615 cm⁻¹,

NMR¹³ C (CDCl₃, TMS): shift in ppm C₂ =144.7; C₃ =103.8; C₄ =55.9 C₅ =33.2; C₆ =204.7; C₇ =115.5 C₈ =75.7

EXAMPLE 4 2-Hydroxy 3-allyloxy 6-methoxy acetophenone [(V), R₁₂ =allyloxy, R₂₂ =OCH₃ ] Code Number 15

With nitrogen scavenging, 0.1 ml of sodium hydride dispersed at 80% in oil is covered by 30 ml of DMF. A solution of 0.12 mole of allylic alcohol in 20 ml of DMF, is added drop by drop, without exceeding 30° C. At the end of adding, agitation is carried out for 1 hour at 20° C. Then 0.025 mole of the compound of code number 13 prepared in example 3 and 0.0026 mole of CuI is added, then agitation is carried out for 1 hour at about 80° C. At the end of the reaction, the reaction medium is poured on 150 ml of water, the pH is adjusted to 3 with dilute hydrochloric acid, it is extracted with ethyl ether, the organic phase is dried on Na₂ SO₄, it is dry evaporated and purified by flash chromatography (eluent: heptane (85)-ethyl acetate (15). Thus the expected compound is isolated with a yield of 45%.

Using a similar method, but from appropriate reagents and using 0.035 mole of Cu₂ O in place of 0.0025 mole of CuI when alkylthioalcohol is used in the place of allylic alcohol, the other compounds (V) are obtained, shown in the following table I, as well as 2-hydroxy 3-methoxy 6-benzyloxy acetophenone [(V), R₁₂ =OCH₃, R₂₂ =OCH₂ φ] of code number 44 (mp=103° C.; IR (KBr): band CO at 1625 cm⁻¹)

                                      TABLE I                                      __________________________________________________________________________      ##STR9##                                    (V)                               Compounds (V) Common spectral data:                                                               IR (KBr):    band CO at 1620 cm.sup.-1                                         NMR .sup.1 H (CDCl.sub.3), TMS):                                                            6.9 and 6.3 ppm, 2d(2H), Ar .sub.--H                                           about 13 ppm, 1s(1H), O .sub.--H                                               3.8 ppm, 1s(3H), OC .sub.--H.sub.3                                             2.6 ppm, 1s(3H), COC .sub.--H.sub.3                            Melting                                                        Code            point                                                          Number                                                                               R.sub.12  (°C.)                                                                          NMR .sup.1 H (CDCl.sub.3, TMS) of the protons of                               R.sub.12                                                __________________________________________________________________________     7b    CH.sub.3 CH.sub.2 O                                                                      70     4 ppm, q(2H), OC .sub.--H.sub.2 CH.sub.3 ; 3 ppm,                              t(3H),                                                                         OCH.sub.2 C .sub.--H.sub.3                              14    CH.sub.3 (CH.sub.2).sub.2 O                                                              90     3.9 ppm, m(2H), OC .sub.--H.sub. 2 R; 1.7 ppm,                                 m(2H),                                                                         OCH.sub.2 C .sub.--H.sub.2 CH.sub.3 ; 1 ppm,                                   m(3H), OCH.sub.2 CH.sub.2 C .sub.--H.sub.3              15    CH.sub.2CHCH.sub.2 O                                                                     oil    from 5 to 6 ppm, m(3H), C .sub.--H.sub.2C .sub.--H;                             4.5 ppm, d(2H),                                                               CH.sub.2CHC .sub.--H.sub.2 O                            16    φCH.sub.2 O                                                                          "                                                                                      ##STR10##                                              17    CH.sub.3 O(CH.sub.2).sub.2 O                                                             63     4 ppm, t(2H), ArOC .sub.--H.sub.2 CH.sub.2 R; 3.7                              ppm, m(5H),                                                                    ArOC .sub.--H.sub.3 + C .sub.--H.sub.2 OCH.sub.3 ;                             3.4 ppm, s(3H), ROC .sub.--H.sub.3                      18    cC.sub.6 H.sub.11 O                                                                      oil    3.9 ppm, s + t(4H), OC .sub.--H.sub.3 + ArOC                                   .sub.--HRR';                                                                   1.5 ppm, m(10H), C .sub.--H.sub.2 cyclohexyl            21    CH.sub.3 S                                                                               83     7.3 ppm, d(1H), (J:8Hz)Ar .sub.--H; 2.3 ppm,                                   s(3H),                                                                         C .sub.--H.sub.3 S                                      22    CH.sub.3 CH.sub.2 S                                                                      57     7.4 ppm, d(1H), (J:8Hz)Ar .sub.--H; 2.8 ppm,                                   q(2H),                                                                         CH.sub.3 C .sub.--H.sub.2 S; 1.2 ppm, d(3H), C                                 .sub.--H.sub.3 CH.sub.2 S                               __________________________________________________________________________

EXAMPLE 5 2-(2-Piperidino ethoxy) 3-methoxy 6-benzyloxy acetophenone [(VII); n=2, p=5] Code Number: 45

A mixture of 0.15 mole of the compound of code number 44 prepared in accordance with example 4, 0.15 mole of N-(2-chloroethyl)-piperidine hydrochloride, 0.46 mole of K₂ CO₃ and 750 ml of acetonitrile is brought to reflux for 2 hours. Then, it is cooled, filtered, dry evaporated, the residue is taken up with 300 ml of ethyl ether, the organic phase is washed with 50 ml of water, dried on Na₂ SO₄ and evaporated. After purification using the usual techniques, the expected compound is obtained with a yield of 87% (IR_(KBr) : CO band at 1710 cm⁻¹).

EXAMPLE 6 2-(2-Piperidino ethoxy) 3-methoxy 6-hydroxy acetophenone [(VI); n=2, p=5] Code Number: 46

To a solution of 30 mmoles of the compound of code number 45 prepared in example 5 in 100 ml of ethanol are added 2 g of 10% palladium on charcoal containing 50% humidity and hydrochoric ethanol traces. Agitation is carried out for 2 hours at 20° C. in a hydrogen atmosphere. Then the medium is filtered, the catalyst is rinsed with ethanol and the medium is dry evaporated so as to obtain the expected compound with a yield of 82%, in the form of a pure oil (IR_(KBr) : CO band at 1640 cm⁻¹).

EXAMPLE 7 O-alkylation in position 6 of the acetophenone of code number 46 prepared in example 6 for obtaining the compounds of formula (IV) where R₁₁ =OCH₃

A mixture of 20 mmoles of the acetophenone 46, 22 mmoles of a compound of formula R₂₁₀ -Y defined in the following table II, 60 mmoles of K₂ CO₃ and 70 ml of acetonitrile is heated to reflux. Once the reaction is finished (4-120 hours), the mixture is dry evaporated, taken up with water, extracted with ethyl ether, the hydrochloride is extracted from the organic phase by 1N HCl, the aqueous phase is washed with ethyl ether, the O-alkylated acetophenone is salted out from the aqueous phase with NH₄ OH, extracted with ethyl ether, dried on MgSO₄, dry evaporated and the oil obtained is filtered on silica (eluent:dichloromethane then ethyl acetate), this oil corresponding to the expected compounds (IV). A number of these compounds are shown in the following table II.

                                      TABLE II                                     __________________________________________________________________________      ##STR11##                                           (IV)                      Compounds (IV) Common spectral data:                                                               IR (KBr):    band CO at 1710 cm.sup.-1                                         NMR .sup.1 H (CDCl.sub.3, TMS):                                                             6.6 ppm, q(2H), Ar .sub.--H                                                    4.1 ppm, t(2H), OC .sub.--H.sub.2CH.sub.2                                      3.7 ppm, s(3H), OC .sub.--H.sub.3                                               ##STR12##                                                                      ##STR13##                                    Code number R.sub.21  R.sub.210Y                                                                             NMR .sup.1 H (CDCl.sub.3), TMS) of the                                         protons of R.sub.21                              __________________________________________________________________________     47          CH.sub.3 (CH.sub.2).sub.3 O                                                              I       4 ppm, m(4H) dont RC .sub.--H.sub.2 O; 1.5                                     ppm, m                                                                         (10H) including CH.sub.3 (C .sub.--H.sub.2).                                   sub.3 O; 1 ppm, m                                                              (3H), C .sub.--H.sub.3                           48          CH.sub.3 (CH.sub.2).sub.2 O                                                              Br      3.9 ppm, m(4H) dont RC .sub.--H.sub.2 O:                                       1.5 ppm,                                                                       m(8H) including CH.sub.3 C .sub.--H.sub.2                                      CH.sub.2 O; 1 ppm, m                                                           (3H), C .sub.--H.sub.3                           49          (CH.sub.3).sub.2 CHO                                                                     Br      4.3 ppm, m(1H), (CH.sub.3).sub.2 C .sub.--HO                                   ; 1.3 ppm,                                                                     d(6H), (C .sub.--H.sub.3).sub.2 CHO              50          CH.sub.3 (CH.sub.2).sub.7 O                                                              OMs     3.8 ppm, m(4H) dont OCH.sub.2 R; 1.4 ppm,                                      m,                                                                             (21H) including OCH.sub.2 (C .sub.--H.sub.2)                                   .sub.6 C .sub.-- H.sub.3                         51          cC.sub.6 H.sub.11 O                                                                      Oms     4.1 ppm, m(3H) including C .sub.--H(CH.sub.2                                   ).sub.5 ; 1.5 ppm,                                                             m(16H) including CH(C .sub.--H.sub.2).sub.5      52          CH.sub.3 CH.sub.2 O                                                                      OSO.sub.3 Et                                                                           4 ppm, m(4H) dont CH.sub.3 C .sub.--H.sub.2                                    O; 1.3 ppm,                                                                    m(9H) including C .sub.--H.sub.3 CH.sub.2        __________________________________________________________________________                                   O                                           

EXAMPLE 8 Preparation of the acetophenones of formula (IV) where R₂₁ =OCH₃

The operating mode used is that described for example 5, but using the compounds (V) as starting products where R₂₂ =OCH₃.

A number of the compounds thus synthesized (which are all in the form of oil) are shown in the following table III.

                                      TABLE III                                    __________________________________________________________________________      ##STR14##                              (IV)                                   Code number                                                                           R.sub.11 Starting compounds                                                                       Remarks -- Special treatments                        __________________________________________________________________________     100    CH.sub.3 CH.sub.2 O                                                                     7b        --                                                   101    CH.sub.3 (CH.sub.2).sub.2 O                                                             14        --                                                   102    CH.sub.2CHCH.sub.2 O                                                                    15        Purification by recristallization                                              of the oxalate in acetone                            103    φCH.sub.2 O                                                                         16        Hydrochloride mp = 180° C.                    104    CH.sub.3 O(CH.sub.2).sub.2 O                                                            17        --                                                   105    cC.sub.6 H.sub.11 O                                                                     18        --                                                   106    CH.sub.3 S                                                                              21        Chromatography                                                                          CH.sub.2 Cl.sub.2                                                                   (95)                                                                      MeOH (4, 5)                                                                    NH.sub.4 OH                                                                         (0, 5)                                 107    CH.sub.3 CH.sub.2 S                                                                     22        Chromatography                                                                          CH.sub.2 Cl.sub.2                                                                   (95)                                                                      MeOH (4, 5)                                                                    NH.sub.4 OH                                                                         (0, 5)                                 __________________________________________________________________________

It should also be noted that for these compounds:

in ¹ H NMR, the peaks corresponding to the aminated ether chain appear at 4 ppm t (2H), ##STR15## 2,5 ppm, m (6H), ##STR16## and 1.5 ppm, m (6H), ##STR17## and in IR, the CO band appears at 1680-1700 cm⁻¹.

EXAMPLE 9 2,3-Dimethoxy 6-bromo benzoic acid (XV) Code Number: 72

91 g (0.5 mole) of 2,3-dimethoxy benzoic acid (XVI) are solubilized in 1.2 l of 1.6N NaOH, cooled to 0° C.; 38.4 ml (0.75 mole) of bromine are added and agitation is carried out for 30 minutes at +5° C.

Then the mixture is acidifed, using HCl, extracted with ethyl ether and the organic phase washed with sodium thiosulphate, dried and evaporated. The residue is taken up in 200 ml of ethanol, 3 drops of sulphuric acid are added and it is left at reflux one night. Then it is dry evaporated, the residue is taken up with 300 ml of ethyl ether, the aqueous phase is extracted with 300 ml of 2N NaOH, the aqueous phase is washed with ethyl ether before being dried on Na₂ SO₄ in the presence of animal black. Then it is filtered, evaporated and dried. Thus, 107 g of the pure expected compound are isolated, which is crystallisable in a petroleum ether (50)-toluene (50) mixture.

mp=87° C.

IR_(KBr) : CO band at 1710 cm⁻¹

mass spectrum: molecular peak at 261

¹³ C NMR (CDCl₃): ##STR18##

EXAMPLE 10 2,3-Dimethoxy 6-bromo benzoic acid chloride (XIV) (Code Number: 73

6.8 mmoles of the acid of code number 72 prepared in the preceding example are agitated with 34 mmoles of thionyl chloride in 5 ml of toluene for 48 hours. Then, the mixture is dry evaporated and the excess thionyl chloride is eliminated by azeotropic distillation of the toluene. The resultant expected compound is used as it is in the method of example 11.

EXAMPLE 11 2,3-Dimethoxy 6-methyl acetophenone (XIII) Code Number: 75

0.250 mole of MnI₂ is dispersed in 800 ml of ethyl ether freshly distilled on LiAlH₄. At 0° C., 0.24 mole of methyllithium (1.6N solution in ethyl ether) is added in 15 minutes, then agitation is carried out for half an hour at 0° C., then for 2 hours at ambient temperature.

Then the reaction medium is cooled to 0° C. and 0.12 mole of the compound of code number 73 prepared in example 10 and diluted with 50 ml of ethyl ether is added. After reaction for half an hour at 0° C., then for 2 hours 30 mins at 25° C., 120 ml of 2N ammonia are added, agitation is carried out for 15 minutes, the reaction mixture is neutralized with hydrochloric acid, extracted with ethyl ether, the organic phase is washed with a thiosulphate solution, then it is dried and dry evaporated. The expected is obtained with a yield of 88%.

IR(KBr): CO band at 1700 cm⁻¹

¹³ C NMR: C₁ =113.3-125.9 ##STR19##

EXAMPLE 12 2,3-Dimethoxy 6-ethyl benzoic acid (XVIII) Code Number: 94

13 g (50 mmoles) of the acid (XV) of code number 72 are dissolved in 160 ml of THF at -100° C. and 67 ml (107 mmoles) of a 1.6N n-butyllithium solution are slowly added. It is left under agitation for 15 minutes and 37.6 ml (500 mmoles) of ethyl iodide are added. It is left for 1 hour at -90° C., then for 1 hour at -60° C. and 1 hour at 20° C. The reaction medium is poured on 2N HCl. The aqueous phase is extracted with ethyl ether. The organic phase is dried and concentrated. The residue is taken up in ethanol with a few drops of H₂ SO₄ and heated to reflux overnight and concentrated. The residue is taken up with the NaOH (2N)-ethyl ether mixture. After extraction, the aqueous phase is acidified with HCl and extracted with ethyl ether. After drying of the organic phase followed by its concentration, 8.24 g of the expected product is obtained in the form of an oil.

IR_(KBr) : CO band: 1700 cm⁻¹

OH band: 3100 cm⁻¹.

EXAMPLE 13 2,3-Dimethoxy 6-ethyl benzoic acid chloride (XVII) Code Number: 97

This compound is prepared using an operating mode similar to that of example 10, but from the compound of code number 94.

Yield: 77%

IR_(KBr) : CO band at 1795 cm⁻¹.

EXAMPLE 14 2,3-Dimethoxy 6-ethyl acetophenone (XIII) Code Number: 98

This compound is prepared using an operating mode similar to that for example 11, but from the compound of code number 97.

IR_(KBr) : CO band at 1705 cm⁻¹.

EXAMPLE 15 2-Hydroxy 3-methoxy 6-methyl acetophenone (XII) Code Number: 92

To a solution of 8.32 g (43 mmoles) of the compound of code number 75 prepared in example 11, in 100 ml of CH₂ Cl₂ at 0° C., 5.7 g (43 mmoles) of AlCl₃ are added, agitation is carried out for 1 hour at 0° C., then 6 hours at reflux. Then the reaction mixture is cooled and it is poured on 50 ml of concentrated hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with water then dried on Na₂ SO₄ and dry evaporated. After purification by chromatography, 5.93 g of a pure yellow oil are obtained which corresponds to the expected compound.

IR_(KBr) : CO band: 1690 cm⁻¹

OH band: 3400 cm⁻¹.

¹³ C NMR: C₂ -C₃ =113.5-121.6 ##STR20##

EXAMPLE 16 2-(2-Piperidino ethoxy) 3-methoxy 6-methyl acetophenone [(IV); n=2, p=5, R₁₁ =OCH₃, R₂₁ =CH₃ ] Code Number: 108

This compound is prepared using an operating mode similar to that of example 5, but from the compound of code number 92 prepared in example 15.

The IR and ¹ H NMR spectra of the compound in question have the characteristics mentioned for example 8.

EXAMPLE 17 2-[2-(2-Tetrahydropyranyloxy) ethoxy]3-benzyloxy 6-methoxy acetophenone (XI) Code Number: 31

5.44 g (20 mmoles) of the compound of code number 16 prepared in accordance with example 4, 4.8 g (29 mmoles) of 2-(2-chloroethoxy) tetrahydropyrane and 8.3 g (60 mmoles) of K₂ CO₃ are heated to reflux for 5 days in acetonitrile. Then the mixture is dry evaporated, the residue is taken up with 25 ml of water, extracted with 35 ml of ethyl ether, dried and evaporated after filtration on silica (eluent: dichloromethane). 3.95 g of the expected compound are recovered which is in the form of an oil.

IR_(KBr) : CO band: 1710 cm⁻¹

EXAMPLE 18 2-[2-(2-Tetrahydropyranyloxy) ethoxy 3-hydroxy 6-methoxy acetophenone (X) Code Number: 32

3.95 g (10 mmoles) of the compound of code number 31 obtained in the preceding example are agitated with 0.8 g of 10% Pd on charcoal containing 50% of water in a hydrogen atmosphere at 20° C. After a night in contact, the catalyst is separated by filtration, rinsed with ethanol and the residue is dry evaporated. Thus, 3.05 g of the expected compound are isolated.

mp=83° C.

IR_(KBr) : CO band: 1700 cm⁻¹

OH band: 3300 cm⁻¹.

EXAMPLE 19 2-(2-Hydroxyethoxy) 3-(2,2,2-trifluoroethoxy) 6-methoxy acetophenone [(IX), R₁₁₀ =OCH₂ CF₃ ] Code Number: 33a

The mixture of 5.75 g (18.5 mmoles) of the compound of code number 32 prepared in the preceding example, 8.6 g (34.4 mmoles) of trifluoroethyl triflate, 7.68 g (55.6 mmoles) of K₂ CO₃ and 60 ml of acetone are heated to reflux. After 3 hours of contact, the mixture is filtered, dry evaporated, taken up with a 3N hydrochloric ethanol (25 ml)-water (25 ml) mixture. After agitation then neutralization with sodium bicarbonate, it is dry evaporated, the evaporation residue is taken up with 50 ml of water, the aqueous phase is extracted with ethyl ether, the extract is dried and dry evaporated. Thus, 4.47 g of the expected compound are obtained in the form of pure oil.

IR_(KBr) : CO band: 1700 cm⁻¹

OH band: 3430 cm⁻¹.

EXAMPLE 20 2-(2-Hydroxyethoxy) 3-isopropyloxy 6-methoxy acetophenone [(IX), R₁₁₀ =OCH(CH₃)₂ ] Code Number: 33b

5.7 g (18.5 mmoles) of the compound of code number 32 obtained in example 18 are dissolved in 60 ml of DMF. 2.23 g (56 mmoles) of powdered NaOH are added, the mixture is warmed to 50° C. and 3.5 ml (37 mmoles) of isopropyl bromide are added. After 2 hours 30 minutes at 50° C., the reaction mixture is poured into 200 ml of water and extracted with twice 200 ml of ethyl ether. The ether phases are agitated for a few minutes with 15 ml of concentrated hydrochloric acid, then washed with water then with a sodium bicarbonate solution, dried and evaporated. Thus, 4.97 g of a pure oil are isolated which correspond to the expected compound.

IR_(KBr) : CO band: 1700 cm⁻¹

OH band: 3350 cm⁻¹.

EXAMPLE 21 2-(2-Mesyloxyethoxy) 3-(2,2,2-trifluoroethoxy) 6-methoxy acetophenone [(VIII), R₁₁₀ =CF₃ CH₂ O] Code Number: 34a

14 mmoles of the compound of code number 33a are dissolved in 50 ml of dichloromethane. 21 mmoles of triethylamine are added, the mixture is cooled to 0° C. and 15 mmoles of mesyl chloride are added very slowly. At the end of addition, agitation is carried out for 30 minutes at 0° C., then the mixture is washed with water, dried on Na₂ SO₄ and dry evaporated. Thus, the expected compound is isolated.

IR_(KBr) : CO band at 1710 cm⁻¹

Using the same method, but from the compound of code number 33b, 2-(2-mesyloxyethoxy) 3-isopropoxy 6-methoxy acetophenone is obtained whose code number is 34b [(VIII), R₁₁₀ =OiPr].

EXAMPLE 22 2-(2-Piperidino ethoxy) 3-(2,2,2-trifluoro ethoxy) 6-methoxy acetophenone [(IV), n=2, p=5, R₁₁ =OCH₂ CF₃, R₂₁ =OCH₃ ] Code Number: 35a

12.9 mmoles of the compound of code number 34a prepared in the preceding example in 500 mmoles of piperadine are brought to boiling point. Then, it is dry evaporated, taken up with ethyl acetate, extracted with 2N HCl, the aqueous phase is washed with ethyl ether, the product of this phase is salted out by the addition of NH₄ OH, then extracted with ethyl acetate. The organic phase is washed several times with water than dried on Na₂ SO₄, filtered and evaporated. Thus, the expected compound is obtained in the form of an oil.

¹ H NMR (CDCl₃, TMS): 6,7 ppm, q(2H), Ar-H; 4.3 ppm, m(4H), Ar-O-CH₂ -CF₃ and Ar-O-CH₂ CH₂ -N; 3.7 ppm, s(3H), OCH₃ ; 2.5 ppm, m(9H), CO-CH₃ and ##STR21##

1.5 ppm, m(6H), ##STR22##

Similarly, but from the compound of code number 34b, 2-(2-piperadinoethoxy) 3-isopropoxy 6-methoxy acetophenone [(IV), n=2, p=5, R₁₁ =OiPr, R₂₁ =OCH₃ ] is obtained whose code number is 35b.

¹ H NMR (CDCl₃, TMS): 6.7 ppm, q(2H), Ar-H; 4.2 ppm, t+m (3H), ArOCH₂ CH₂ N+ArOCH(CH₃)₂ ; 1.4 ppm, d+m (12H), (CH₂)₃ +CH(CH₃)₂

EXAMPLE 23 1-[2-2-Piperidino ethoxy) 3-allyloxy 6-methoxy phenyl] 3-(4-hydroxyphenyl) 2-propen 1-one [(III), n=2, p=5, R₁₁ =allyloxy, R₂₁ =OCH₃, R₃ =H] Code Number: 125

7.7 g (23 mmoles) of the compound of code number 102 prepared in accordance with example 8 are solubilized in 100 ml of ethanol, 3.1 g (25 mmoles) of 4-hydroxy benzaldehyde and 4.6 g (110 mmoles) of 50% aqueous NaOH are added and then the mixture is agitated at 20° C. for 3 days. Then the alcohol is evaporated, the residue is taken up with water, washed with isopropyl ether, acidifed with hydrochloric acid (the hydrochloride precipitates), the heterogeneous aqueous phase is washed with isopropyl ether, the aqueous phase is treated with 50 ml of 5N NH₄ OH, extracted with ethyl acetate, then the organic phase is dried, evaporated and the product obtained is crystallized in 50 ml of ethyl acetate. Thus, 6.03 g of the expected compound are isolated.

mp=132° C.

IR_(KBr) : CO band: 1650 cm⁻¹

OH band: 3400 cm⁻¹

Using the same operating method, but from appropriate reagents, the compounds of code numbers 120, 122 and 126 shown in the following table IV are obtained.

EXAMPLE 24 1-[2-(2-Piperidino ethoxy) 3-methoxy 6-benzyloxy phenyl] 3-{4-[(2-tetrahydropyranyl)oxy] phenyl} 2-propen 1-one [(III), n=2, p=5, R₁₁ =OCH₃, R₂₁ =OCH₂ φ, R₃ =2-tetrahydropyranyl] Code Number: 114

56.6 g (148 mmoles) of the compound of code number 45 prepared in example 5 and 30 g (148 mmoles) of 4-(2-tetrahydropyranyl)oxy benzaldehyde are dissolved in 600 ml of ethyl alcohol. Then, 37 ml (370 mmoles) of 10N aqueous NaOH are added, agitation is carried out for 5 hours at 25° C., the alcohol is concentrated to 3/4, the reaction mixture is poured in 1 liter of water, extracted with twice 200 ml of CH₂ Cl₂, the organic phase is washed with three times 200 ml of water, dried and evaporated. The expected product is crystallized in ethyl ether and thus 65 g of the expected compound are isolated.

mp=103° C.

IR_(KBr) : CO band at 1650 cm¹

Using the same method, but from the appropriate reagents, the compounds of code numbers 110, 114-119, 124 and 127-131 shown in table IV herebelow are obtained.

                                      TABLE IV                                     __________________________________________________________________________      ##STR23##                                 (III)                                                        Code No. of                                                                           Melting                                        Code                     the starting                                                                          point                                                                               Purification                              number                                                                              R.sub.11  R.sub.21                                                                              R.sub.3                                                                           compound                                                                              (°C.)                                                                        treatments                                __________________________________________________________________________     110  CF.sub.3 CH.sub.2 O                                                                      CH.sub.3 O                                                                            H   35a   oil  Filtered on silica                        114  CH.sub.3 O                                                                               BzO    THP                                                                                45    103  Crist. in Et.sub.2 O                      115  CH.sub.3 O                                                                               CH.sub.3 (CH.sub.2).sub.3 O                                                           Bz  47    oil  --                                        116  CH.sub.3 O                                                                               CH.sub.3 (CH.sub.2).sub.2 O                                                           Bz  48    "    --                                        117  CH.sub.3 O                                                                               (CH.sub.3).sub.2 CHO                                                                  Bz  49    "    --                                        118  CH.sub.3 O                                                                               CH.sub.3 (CH.sub.2).sub.7 O                                                           Bz  50    "    --                                        119  CH.sub.3 O                                                                               cC.sub.6 H.sub.11 O                                                                   Bz  51    "    --                                        120  CH.sub.3 O                                                                               CH.sub.3 CH.sub.2 O                                                                   H   52    124  Crist. in Et.sub.2 O                      122  CH.sub.3 CH.sub.2 O                                                                      CH.sub.3 O                                                                            H  100    153  Crist. in Et.sub.2 O                      124  CH.sub.3 (CH.sub.2).sub.2 O                                                              CH.sub.3 O                                                                            Bz 101    oil  --                                        125  CH.sub.2CHCH.sub.2 O                                                                     CH.sub.3 O                                                                            H  102    132  Crist. in AcOEt                           126  BzO       CH.sub.3 O                                                                            H  103    137  Crist. in AcOEt                           127  CH.sub.3 O(CH.sub.2).sub.2 O                                                             CH.sub.3 O                                                                            Bz 104    oil  Filtered on silica                        128  cC.sub.6 H.sub.11 O                                                                      CH.sub.3 O                                                                            Bz 105    "    Filtered on silica                        129  CH.sub.3 S                                                                               CH.sub.3 O                                                                            THP                                                                               106     88  Chromat. then                                                                  crist./iPr.sub.2 O                        130  CH.sub.3 CH.sub.2 S                                                                      CH.sub.3 O                                                                            THP                                                                               107    oil  Filtered on silica                        131  CH.sub.3 O                                                                               CH.sub.3                                                                              Bz 108    "    Filtered on silica                        --   CH.sub.3 O                                                                               C.sub.2 H.sub.5                                                                       Bz --     "    --                                        __________________________________________________________________________      THP = 2tetrahydropyranyl                                                       Bz = benzyl                                                              

EXAMPLE 25 Reduction of the compounds (III) for which R₃ =H, prepared in the preceding example, for obtaining the corresponding compounds (I)

10 mmoles of compound (III) with R₃ =H are dissolved in 150 ml of ethanol. 50 mmoles of pyridine and 25 mmoles of 10N NaOH are added and the mixture is brought to reflux. Then, 50 to 100 mmoles of sodium borohydride are added in 3 hours. At the end of the reaction, the reaction mixture is poured on 700 ml of iced 0.5N HCl, agitation is carried out for 30 minutes at 0° C., then the product is salted out with ammonia, extracted with CH₂ Cl₂, the organic phase is washed with water, dried on Na₂ SO₄, evaporated, purified by flash chromatography [eluent: CH₂ Cl₂ (95)-CH₃ OH (4.5)-NH₄ OH (0.5)], crystallized in ethyl acetate and recrystallized if required in ethanol.

Using this method, the compounds of code numbers 167 and 168 shown in the following table V are obtained, respectively from the compounds of code numbers 125 and 126.

EXAMPLE 26 Reduction of the compounds (III) for which R₃ =2-tetrahydropyranyl, prepared in example 24, for obtaining the corresponding compounds (I)

10 mmoles of compound (III) with R₃ =2-tetrahydropyranyl are heated to reflux in 100 ml of ethanol containing a drop of NaOH. 50 mmoles of sodium borohydride are added in 3 hours, then the medium is cooled, dry evaporated, the residue is taken up with 150 ml of ethyl acetate, poured on 10 ml of HCl at 0° C., the mixture is agitated for 15 minutes, then salted out by ammonia, extracted with three times 120 ml of ethyl acetate, the organic phase is washed with a sodium chloride saturated solution, dried on Na₂ SO₄, dry evaporated and purified by flash chromatography [eluent: CH₂ Cl₂ (97)-CH₃ OH (2.7)-NH₄ OH (0.3)]

Using this method the compounds of code numbers 146, 174 and 175 shown in the following table V were obtained respectively from the compounds of code numbers 114, 129 and 130.

EXAMPLE 27 Reduction of the compounds (III) prepared in example 24 for obtaining the corresponding compounds (I) First Step Preparation of the Compounds (II)

10 mmoles of the compounds (III) are dissolved in an ethyl alcohol (50) ml-THF (50 ml) mixture, 20% by weight of 10% Pd on charcoal containing 50% humidity is added, and agitation is carried out at 20° C. in a hydrogen atmosphere. At the end of the reaction, the catalyst is separated by filtration, rinsed with THF, the mixture is dry evaporated and recrystallized in an appropriate solvent.

Thus, the compounds (II) shown in table VI below are obtained.

Second Step Reduction of the Compounds (II) into the Corresponding Compounds (I)

10 mmoles of compounds (II) obtained in the preceding step are dissolved in 50 ml of ethanol, 1 ml of 10N NaOH (i.e. 10 mmoles) is added, the mixture is heated to reflux and then from 50 to 100 mmoles of sodium borohydride are added in 3 hours. At the end of the addition, the mixture is maintained at reflux for 2 hours, cooled, dry evaporated, taken up with ethyl acetate, poured on 25 ml of 2N HCl at 0° C., agitated for 15 minutes at 0° C., neutralized with NH₄ OH, extracted with twice 100 ml of ethyl acetate, dried, dry evaporated, chromatographed on silica if necessary [eluent: CH₂ Cl₂ (95)-CH₃ OH (4.5)NH₄ OH (0.5)], crystallized and recrystallized if required.

Thus, the compounds (I) are shown in table V other than those of code numbers 146, 167, 168, 174 and 175.

                                      TABLE V                                      __________________________________________________________________________      ##STR24##                                   (I)                               Code number                                                                           R.sub.1    R.sub.2                                                                               Melting point (°C.)                                                               Recrystallization solvent                   __________________________________________________________________________     137    CF.sub.3 CH.sub.2 O                                                                       CH.sub.3 O                                                                            117       Et.sub.2 O                                  146    CH.sub.3 O BzO    153       CH.sub.3 OH                                 148    CH.sub.3 O OH     153       AcOEt                                       150    CH.sub.3 O CH.sub.3 (CH.sub.2).sub.3 O                                                           123       AcOEt                                       152    CH.sub.3 O CH.sub.3 (CH.sub.2).sub.2 O                                                           124       Et.sub.2 O                                  154    CH.sub.3 O (CH.sub.3).sub.2 CHO                                                                  140       iPr.sub.2 O                                 156    CH.sub.3 O CH.sub.3 (CH.sub.2).sub.7 O                                                           113       iPr.sub.2 O                                 158    CH.sub.3 O cC.sub.6 H.sub.11 O                                                                   157       AcOEt                                       160    CH.sub.3 O CH.sub.3 CH.sub.2 O                                                                   148       AcOEt                                       164    CH.sub.3 CH.sub.2 O                                                                       CH.sub.3 O                                                                            119       AcOEt                                       166    CH.sub.3 (CH.sub.2).sub. 2 O                                                              CH.sub.3 O                                                                             99       iPr.sub.2 O                                 167    CH.sub.2CHCH.sub.2O                                                                       CH.sub.3 O                                                                            131       AcOEt                                       168    BzO        CH.sub.3 O                                                                            148       EtOH                                        169    OH         CH.sub.3 O                                                                            134       AcOEt                                       171    CH.sub.3 O(CH.sub.2).sub.2 O                                                              CH.sub.3 O                                                                            110       Et.sub.2 O                                  173    cC.sub.6 H.sub.11 O                                                                       CH.sub.3 O                                                                            142       AcOEt                                       174    CH.sub.3 S CH.sub.3 O                                                                            155       iPrOH                                       175    CH.sub.3 CH.sub.2 S                                                                       CH.sub.3 O                                                                            117       AcOEt                                       177    CH.sub.3 O CH.sub.3                                                                              170       CH.sub.2 Cl.sub.2                           --     CH.sub.3 O C.sub.2 H.sub.5                                                                       136       Et.sub.2 O                                  __________________________________________________________________________

                                      TABLE VI                                     __________________________________________________________________________      ##STR25##                                (II)                                 Code number                                                                           R.sub.10                                                                               R.sub.20                                                                               Melting point (°C.)                                                               Recrystallization solvent                     __________________________________________________________________________     136    CF.sub.3 CH.sub.2 O                                                                    CH.sub.3 O                                                                             oil       --                                            147    CH.sub.3 O                                                                             OH      104       C.sub.2 H.sub.5 OH                            149    CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.3 O                                                            131       Acetone                                       151    CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.2 O                                                            142       "                                             153    CH.sub.3 O                                                                             (CH.sub.3).sub.2 CHO                                                                   157       "                                             155    CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.7 O                                                            oil       --                                            157    CH.sub.3 O                                                                             cC.sub.6 H.sub.11 O                                                                    107       Isopropyl ether                               159    CH.sub.3 O                                                                             CH.sub.3 CH.sub.2 O                                                                    120       "                                             163    CH.sub.3 CH.sub.2 O                                                                    CH.sub.3 O                                                                             115       "                                             165    CH.sub.3 (CH.sub.2).sub.2 O                                                            CH.sub.3 O                                                                             oil       --                                            170    CH.sub.3 O(CH.sub.2).sub.2 O                                                           CH.sub.3 O                                                                             100       Isopropyl ether                               172    cC.sub.6 H.sub.11 O                                                                    CH.sub.3 O                                                                             154       Ethyl ether                                   176    CH.sub.3 O                                                                             CH.sub.3                                                                               oil       --                                            --     CH.sub.3 O                                                                             C.sub.2 H.sub.5                                                                        oil       --                                            __________________________________________________________________________

The compounds (I) and their pharmacologically acceptable salts have been studied on laboratory animals and have shown pharmacological activities and particularly a calcium antagonistic activity.

The calcium antagonistic activity was shown by the test of the contractions of the removed basilar artery of a rabbit in a hyperpotassic medium as described by K. Towart, S. Kazda in Nimodipine Pharmacological Properties edited by P. E. Betz, K. Deck and F. Hoffmeister (1984), publisher: E. K. Schattauer Verlag.

The protocol of this test is the following. The rabbit is anaesthetized with pentobarbital at a dose of 30 mg/kg then sacrificed by exsanguination and decapitated at the third cervical vertebra. The basilar artery is removed (1.5 cm) between the vertebral arteries and the Willis's polygon. The basilar artery is then cut in a spiral at an angle of 45°. It is fixed by means of a curved needle between an L shaped glass support and a movement sensor (Grass, type FT03). A mechanical tension of 500 mg is applied to the vessel, before letting it reach its equilibrium condition.

For a period of 1 hour, the vessel is rinsed every 20 minutes, until a stable level is obtained.

The tonic contraction following depolarization caused by KCl is dependent on the calcic movements for it is abolished by the suppression of calcium in the survival medium.

The concentrations (in nM) are measured which reduce by 50% the amplitude of the contraction induced by the KCl at 35 mmoles.

The results obtained with some compounds of the invention in the preceding test are shown, by way of example, in the following table VII which further shows the acute toxicity (LD 50) of some of the compounds tested and which is estimated on mice using the method of J. T. LITCHFIELD and F. WILCOXON, J. Pharmacol. Exp. Ther. 1949, 96, 99.

                  TABLE VII                                                        ______________________________________                                         Code                    LD.sub.50 Mice                                         number        IC.sub.50 (nM)                                                                           (mg/kg/i.v.)                                           ______________________________________                                         169           >100                                                             164             24      17                                                     137           >100                                                             166            120                                                             167             53                                                             171           >100                                                             173           >100                                                             168           >100                                                             174             27      22                                                     175             31                                                             148           >100                                                             160             6       11,7                                                   154             13                                                             152             10                                                             158           >100                                                             150            100      21,5                                                   156           >100      27,5                                                   146           >100                                                             177             30                                                             ______________________________________                                    

Taking into account the foregoing, the compounds (I) and their pharmaceutically acceptable salts find their use in human or animal therapeutics for treating affections related to a disturbance of the intra and extra cellular movements of calcium at the cerebral level and particularly for treating the troubles of the cerebrovascular system, such as cerebral hemorrhages, cerebral infarct and migraine.

Another object of the present invention consists then in the use of the compounds of the invention for preparing medicaments for treating the above mentioned affections and particularly pharmaceutical compositions which comprise at least one of these compounds in association with a physiologically acceptable support or excipient appropriate for said compounds.

These compositions may for example be formulated for oral, parenteral or rectal administration.

For oral administration, said compositions may be in the form of tablets, sugar-coated pills or capsules prepared by the usual techniques using known supports and excipients such as binding agents, fillers, lubricants and disintegration agents; they may also be in the form of solutions, syrups or suspensions.

For parenteral administration, the compositions of the invention may be in the form of injectable solutions, suspensions or emulsions comprising a liquid, oily or aqueous vehicle, parenterally acceptable.

Finally, for rectal administration, the compositions of the invention may be in the form of suppositories comprising the usual bases for suppositories.

The dose at which the active ingredients, namely the compounds of the invention, may be administered to man or any hot blooded animal, depends more particularly on the type of administration, the body weight and the pathological state of the patient and the therapeutical power of the compounds used. Generally, when taken orally, the doses may reach 500 mg of active ingredient per day (divided into one or more doses); parenterally, the doses may reach 100 mg of active ingredient per day (in one or more daily injections) and rectally, the doses may reach 300 mg of active ingredient per day (in one or more suppositories). 

We claim:
 1. Compounds of the general formula: ##STR26## in which: R₃ is hydrogen, 2-tetrahydropyranyl or benzyl R₁₁ and R₂₁ are such that:either R₁₁ =methoxy, in which case R₂₁ is a group chosen from the following: C₁ -C₄ alkyl; C₂ -C₈ alkyloxy; C₅ -C₇ cycloalkyloxy; benzyloxy; or R₂₁ =methoxy, in which case R₁₁ is a group chosen from the following: C₂ -C₇ alkyloxy; C₂ -C₈ alkyloxy substituted by a methoxy group; C₁ -C₄ trifluoroalkyloxy; C₃ -C₄ alkenyloxy; C₅ -C₇ cycloalkyloxy; benzyloxy; C₁ -C₄ alkylthio; n=2 or 3; and p=4, 5 or
 6. 2. A compound according to claim 1, in which R₁₁ is a member selected from the group consisting of CF₃ CH₂ O, CH₃ O, CH₃ CH₂ O, CH₂ ═CHCH₂ O and C₆ H₅ O, R₂₁ is a member selected from the group consisting of CH₃ O, and CH₃ CH₂ O, R₃ is H, n is 2 and p is
 5. 3. A compound according to claim 2, in which R₁₁ is CF₃ CH₂ O and R₂₁ is CH₃ O.
 4. A compound according to claim 2, in which R₁₁ is CH₃ O and R₂₁ is CH₃ CH₂ O.
 5. A compound according to claim 2, in which R₁₁ is CH₃ CH₂ O and R₂₁ is CH₃ O.
 6. A compound according to claim 2, in which R₁₁ is CH₂ ═CHCH₂ O and R₂₁ is CH₃ O.
 7. A compound according to claim 2, in which R₁₁ is C₆ H₅ O and R₂₁ is CH₃ O. 